A defective gene normally found in blood cancers could be treated with drugs already available for cancers with similar gene defects, scientists at BHP founder-member the University of Birmingham and Queen’s University Belfast have revealed.

The research team, funded mainly by Cancer Research UK and the Medical Research Council, found that tumours with mutations in the SF3B1 gene respond to PARP inhibitors – a type of drug used to treat cancers which have similar mutations in the BRCA1 and BRCA2 genes.

The researchers believe that PARP inhibitors could be used to treat patients with tumours carrying the defective SF3B1 gene. This mutation is most often found in blood cancers, including chronic lymphocytic leukaemia, as well as some rare cancers like uveal melanoma.

Co-author Professor Grant Stewart, of the University of Birmingham, said: “Our work demonstrates that a molecular understanding of how a specific gene mutation affects a cancer cell’s ability to repair damaged DNA can be exploited clinically to specifically tailor the anti-cancer therapy used to treat an individual’s tumour. This will increase the effectiveness of the therapy and hopefully, reduce the chances of re-occurrence.”

Dr Kienan Savage, lead author and Reader at Queen’s University Belfast, said: “Our findings have clinical implications for the treatment of many cancers. We specifically focused on this genetic mutation as it is found in several difficult to treat leukaemias and other cancers, and it affects so many cancer patients. By deepening our understanding of this gene mutation, we have identified new ways of treating these cancers that could improve survival rates.”

PARP inhibitors, which include olaparib and rucaparib, are used to treat some patients with ovarian, breast, prostate and pancreatic cancers – usually patients who have inherited a faulty BRCA1 or BRCA2 gene. Around 1 in 400 people have a faulty BRCA1 or BRCA2 gene.

The research – published in Cancer Research, a journal of the American Association for Cancer Research – found that the SF3B1 mutation produces similar effects to the faulty BRCA1 gene by damaging DNA, preventing it from being repaired properly, and stopping it from making normal copies of itself. PARP inhibitors target the cell’s DNA repair tools by locking them in place on the DNA. This stops DNA repair, causing the cancer cells to die.

The scientists found that cancer cells with the SF3B1 mutation were sensitive to olaparib, the most common PARP inhibitor, some specific chemotherapies and to radiotherapy. The scientists believe that the SF3B1 mutation disrupts the cell’s ability to make DNA repair proteins, leaving it vulnerable to drugs which target these proteins.

The SF3B1 mutation occurs in up to 30% of blood cancers called myelodysplastic syndromes, where blood cells don’t form properly. They are difficult to treat as they occur predominantly in older patients who may not be considered fit for treatment. The mutation is also common among uveal melanoma or cancers of the eye, which currently have limited treatment options.

Dr Katrina Lappin, of Queen’s Univesity Belfast and first author of the study, added: “Our research shows that cancers with these specific mutations, may be treated effectively with PARP inhibitor therapy drugs, which are less toxic, better at killing cancer cells with these mutations and can be taken at home in tablet form. This could have huge implications for improving outcomes and quality of life of people with these cancers. This work will pave the way for clinical trials using PARP inhibitors for the treatment of patients with this commonly associated cancer mutation, allowing a more personalised approach to the treatment of these cancers.”

The researchers now want to test PARP inhibitors in clinical trials with patients who have the SF3B1 mutation to see if they can stop their cancer from spreading.

Michelle Mitchell, Chief Executive of Cancer Research UK, said: “Our scientists helped to discover the BRCA gene over 25 years ago and since then we’ve led the way in developing PARP inhibitors to treat cancers with BRCA gene faults. It’s really exciting to hear about a new mutation, which behaves like the BRCA1 mutation and could in the future be treated in the same way. With PARP inhibitors already widely available, there is huge potential to help people with some of the rarest and most difficult-to-treat cancers known to us. Over the past two decades, PARP inhibitors have saved thousands of lives worldwide, and it will be interesting to see if this research in the future could lead to a similar impact for people with rarer cancers.”

The research was funded by the UK Medical Research Council, Cancer Research UK, Blood Cancer UK, Leukaemia and Lymphoma NI and Great Ormond Street Hospital Children’s Charity.

BHP founder-member University Hospitals Birmingham is the first site in the UK to treat a uveal melanoma patient with the new therapy Tebentafusp outside a clinical trial. Uveal melanoma is a rare cancer situated within the eye. This initiative is being led by Dr Leila Khoja, Immunotherapy lead for the Birmingham Experimental Cancer Medicine Centre (ECMC) and senior clinical lecturer at another of BHP’s founder members, the University of Birmingham.

Developed by Immunocore PLC, Tebentafusp is a bispecific immunotherapy drug, a type of advanced therapy. Immunotherapies harness the body’s immune system to fight cancer, helping it to attack it and to prevent tumours from growing. However, in some tumours the immune response is inadequate to control the tumour and, even in tumours that respond, resistance to treatment can develop. Tebentafusp’s mechanism of action enables it to attach to the tumour and simultaneously to T-cell immune cells. This means that it is able to pull in and activate tumour specific T-cells in hard to treat tumours.

Birmingham participated in the phase II study of Tebentafusp, and the results were published in Clinical Cancer Research. This led to a phase III trial, where it was shown to offer patients better outcomes in terms of survival, when compared with standard drugs offered by their clinical teams.  It is the first drug of this type for a solid tumour that has been proven to offer this benefit to patients. Regulatory approval for Tebentafusp is in process, but the drug is currently available through a compassionate use programme.

Transferring Tebentafusp into standard clinical care for patients with solid tumours is challenging, as specialist pharmacy, nursing and junior doctor skills are required. Hospitals also need to have sufficient capacity to deliver infusions of the drug on an inpatient basis, as the dose is increased over a three week period, before it can be provided on an outpatient basis. The development of this programme will create a model for similar therapies in the future, and Birmingham ECMC is currently facilitating the setup of clinical trials in this field.

These initiatives underline the importance of the Birmingham ECMC and Midlands Wales Advanced Therapy Treatment Centre (MW-ATTC) networks in supporting the delivery of the innovative therapies of the future, training staff and providing the infrastructure required.

Leading scientists at BHP founder-member the University of Birmingham have discovered a previously unknown pathway that prevents specific drugs from working in patients with bowel cancer.

The research findings pave the way for increasing the number of bowel cancer patients who can be successfully treated, say the scientists.

Bowel cancer, also called colorectal cancer, affects the large bowel, which is made up of the colon and rectum. It is the fourth most common cancer in the UK, with over 42,000 people diagnosed with bowel cancer every year in the UK. It is also the second biggest cancer killer, with 16,000 people with bowel cancer dying in the UK every year.

The University of Birmingham-led research involved the study of 184 tumour samples and medical records of bowel cancer patients participating in the COIN trial, as well as research carried out in mice, cell cultures, and a laboratory model for pre-malignant colorectal cancer.

Co-senior author Andrew Beggs, Professor of Cancer Genetics & Surgery at the University of Birmingham, explained: “About 60% of bowel cancers are sensitive to drugs called anti-EGFR inhibitors which work by blocking a key pathway in these cancers.

“However, despite this, in cancers that should be sensitive to them, these drugs only work in patients about 50% of the time.”

Co-senior author Dr Fedor Berditchevski, also of the University of Birmingham, added: “Scientists have previously found that if bowel cancer patients have a mutation in a gene called RAS, the anti-EGFR inhibitors will not work.

“However, our research has now discovered a new pathway involving a tetraspanin protein called TSPAN6 that is frequently inactive in bowel cancer patients and this makes these drugs less effective. Crucially, our research also shows that if this pathway is active in a patient’s cancer then the drug will work, irrespective of whether they have a mutation in RAS or not.”

First author Dr Regina Andrijes, a Postdoctoral Fellow at the University of Birmingham, concludes: “This is the first time a tetraspanin protein has been shown to be directly involved with bowel cancer. Our research findings show that this new pathway could act as a biomarker for treatment with anti-EGFR drugs in bowel cancer, increasing a patient’s chance of survival and the number of patients who could benefit from these drugs who previously would not have.”

The researchers are now set to undertake a clinical trial of using this marker to better identify patients for anti-EGFR treatment.

The study, published in the Proceedings of the National Academy of Sciences (PNAS), was carried out in collaboration with fellow BHP member University Hospitals Birmingham NHS Foundation Trust, working with Semmelweis University in Hungary, and Assiut University in Egypt.